ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.223dup (p.Tyr75fs)

dbSNP: rs398123146
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen RCV004800277 SCV005620254 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2025-01-07 reviewed by expert panel curation The NM_000070.3: c.223dup p.(Tyr75LeufsTer5) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 1/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least four individuals with LGMD (PMID: 27854218, 30564623; LOVD CAPN3_000537). In at least one case, the variant was identified in unknown phase with a pathogenic variant (c.2362_2363delinsTCATCT p.(Arg788fsTer14), 0.5 pts, LOVD Individual #00220184) (PM3_Supporting), and at least one patient with this variant displayed progressive limb girdle muscle weakness (PP4). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): PVS1, PM3_Supporting, PP4, PM2_Supporting.
Eurofins Ntd Llc (ga) RCV000790766 SCV000224138 pathogenic not provided 2015-12-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000173057 SCV000766718 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-07-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr75Leufs*5) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 92411). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000790766 SCV005325915 pathogenic not provided 2023-11-22 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27854218, 15689361, 10330340, 19556129, 31589614, Schiava2022[casereport], 31931849, 30564623)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004800277 SCV005422940 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2024-10-08 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.223dupT (p.Tyr75LeufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 249924 control chromosomes (gnomAD). c.223dupT has been reported in the literature in at least an individual affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Punetha_2016). The following publication have been ascertained in the context of this evaluation (PMID: 27854218). ClinVar contains an entry for this variant (Variation ID: 92411). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000173057 SCV001461303 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-09-16 no assertion criteria provided clinical testing
Baylor Genetics RCV003460739 SCV004213749 pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2023-07-21 flagged submission clinical testing

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